The critical period with respect to teratogenic effects is during organogenesis. This starts at about 17 days after conception and is complete by 60 to 70 days. Exposure to certain drugs during this period (17 to 70 days) can cause major birth defects.
Some drugs can interfere with functional development of organ systems (eg central nervous system, integumentary system, cardiovascular system) in the second and third trimesters and produce serious consequences.
It is quite possible that a woman may not be aware of her pregnancy until after the early stages of organogenesis. For this reason, drugs in the most severe category of risk should not be prescribed to a woman of childbearing potential, unless a pregnancy test is negative and she is using an effective method of contraception.
Caffeine
Women taking opioids chronically should probably be delivered in an appropriate tertiary hospital, where development in the neonate of a withdrawal syndrome will be prevented if possible, and managed as necessary.
Increased drug concentration in the vicinity of the fetus resulting from the topical application of drugs to the genital mucosa of pregnant women should also be considered.
All antiepileptic drugs are potentially teratogenic and there is no ‘drug of choice’ in pregnancy. However, many women with epilepsy need to be continued on antiepileptic drugs to prevent the potentially harmful effects of uncontrolled seizures to them, to their unborn child, and to others. In general, the best choice of treatment is the drug that best controls the epilepsy, at the lowest effective dose, in monotherapy if possible. Changes to the treatment regimen, including attempts to withdraw medications, are best done preconception.
Overall, the risk of teratogenicity is probably greatest with sodium valproate, particularly doses greater than 1200 mg/day, and phenobarbitone.
Sodium valproate has been associated with up to a ten-fold (0.2% to 2%) increased risk of spina bifida, as well as other serious malformations and coagulopathies. These effects are thought to be dose-related.
Carbamazepine has also been associated with significant increased risk of spina bifida in addition to developmental delay and craniofacial defects, although the risk is lower than with higher dose sodium valproate.
Data are now accumulating which suggest that lamotrigine (if taken alone) may not be associated with increased risk of congenital abnormalities if used in early pregnancy. Lamotrigine clearance may be increased by 50% in pregnancy requiring increased dose, with corresponding dose reduction after delivery
Phenytoin has been associated with distinctive craniofacial abnormalities, mental and growth deficiency and, less frequently, oral clefts and cardiac anomalies.
Primidone, phenobarbitone or methylphenobarbitone, alone or in combination with other antiepileptic drugs, can cause coagulation defects in the neonate, which may be preventable by the administration of vitamin K to the mother prior to delivery.
The newer antiepileptic drugs, with the exception of lamotrigine, do not have enough data available to inform on their risk profile for birth defects, and therefore a decision on whether to continue these in a woman planning to become pregnant needs to balance the potential risk versus the potential benefit in seizure control.
Women taking antiepileptic drugs should be offered counselling (preferably preconception) and prenatal screening (alpha-fetoprotein measurement and ultrasound examination). If a decision is taken to continue antiepileptics, authorities suggest that the risk of neural tube defects may be reduced if larger than the standard dose of folic acid is taken prior to pregnancy (ie 5 mg/day instead of 0.5 mg/day) although this is not established to definitely reduce the risk. Phytomenadione (vitamin K1), taken from 36 weeks of pregnancy (20 mg/day ‘Konakion’ chewable tablets) has also been suggested to reduce the risk of coagulopathies in women using medications that induce the liver drug metabolising enzymes (eg carbamazepine, phenytoin, phenobarbitone).
Plasma antiepileptic drug concentrations may change during pregnancy, so concentrations should be measured preconception, during pregnancy, and over the first 3 months postpartum. Changes during and after pregnancy may be helpful in assessing the effect of the pregnancy on the woman’s pharmacokinetic profile for the drug, and therefore help guide decisions about dose adjustment. This is particularly important for lamotrigine, as the kinetics of lamotrigine are altered to such an extent that dose adjustments are usually required during pregnancy.
Lamotrigine plasma levels decrease in pregnancy because of increased hepatic drug clearance, which is induced by physiological changes during pregnancy. Studies have shown that the ratio of dose to plasma concentration is 5.8 times higher at delivery and 3.6 times higher in late pregnancy as compared with 5 months postpartum.
It is recommended that a women’s plasma level of lamotrigine be measured prior to conception, or as early as possible into the pregnancy, so that a baseline can be established. Thereafter, the plasma levels of lamotrigine should be measured at least bimonthly throughout the pregnancy, and dose adjustments guided by plasma levels. Following parturition, maternal lamotrigine kinetics normalise in 2 to 3 weeks.
For acute treatment, paracetamol is safe but often inadequate for severe attacks. Many women have used aspirin and ibuprofen in early pregnancy but safety cannot be assured. Both aspirin and ibuprofen (but particularly aspirin) should not be used in late pregnancy, as these drugs may inhibit closure of the fetal ductus arteriosus; aspirin may also affect platelet function.
Parenteral opioids, such as morphine, are probably safe but should be reserved for severe attacks. Repeated doses of pethidine can lead to the accumulation of a toxic metabolite, with resultant confusion and seizures. Repeated doses of opioids can lead to dependency and withdrawal symptoms in the mother and newborn.
For prophylaxis, propranolol and metoprolol have also been used but again safety cannot be assured. Beta blockers in late pregnancy may be associated with fetal bradycardia, hypoglycaemia and respiratory depression.
The safety of the atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone and ziprasidone) has yet to be established. However, on the basis of case reports and small series, there are no consistent reports of deleterious effects on the fetus. The most data is available for olanzapine and no increased risk has emerged. Isolated case reports of congenital abnormalities have been reported following clozapine use during pregnancy, but no definitive association has been established.
Unlike typical antipsychotics, some atypical antipsychotics (eg clozapine, quetiapine, aripiprazole) do not increase prolactin, and others (eg olanzapine) are less likely to increase prolactin, and hence are less likely to reduce women’s fertility. When changing from a typical to an atypical antipsychotic, warning women about this normalisation of their fertility is warranted.
Typical antipsychotics
On the basis of the limited data available, these drugs appear to present no serious problems, with the possible exception of chlorpromazine, for which some evidence suggests a small increased risk of congenital abnormalities. However, larger doses of any of these drugs, especially when given continuously, may cause protracted withdrawal dyskinesias in the neonate.
Treatment of extrapyramidal adverse effects
Anticholinergics have Category B classifications and there is inconclusive evidence that they may have been associated with an increase in congenital abnormalities in some studies, as well as neonatal adverse effects. They should be avoided if possible in pregnancy. Beta-blockers may relieve akathisia, however possible cardiovascular adverse effects need to be taken into account.
In the case of selective serotonin reuptake inhibitors (SSRIs), there is no evidence of increased malformation or growth retardation in humans; however, data are limited. If the patient is already on an SSRI and is well-controlled and becomes pregnant, the need for ongoing medication should be re-evaluated, however changing to another antidepressant is not indicated.
Data on the safety of fluoxetine is more extensive than for other SSRIs. However, accumulating data on the latter pose no cause for concern at this stage. The very long half-life of fluoxetine (in the neonate) needs to be considered. Some authorities recommend reducing the dose of fluoxetine by 30% to 50% ten to fourteen days prior to delivery. However, the risk of relapse of depression has to be weighed against this.
Very recently, several reports have been published describing serotonergic effects in some neonates whose mothers were taking SSRIs prior to delivery. The true incidence of these effects remains unclear. Agitation/jitteriness, diarrhoea and poor feeding are the most consistent problems reported. Whether these are withdrawal or toxic effects remains uncertain. The problems have usually resolved in a few days, and none have lasted longer than 2 weeks. Paroxetine and fluoxetine have been associated with such effects in some neonates. However, the potential benefits of utilising shorter half-life SSRIs (in the lowest effective dose) in depressed pregnant women may well outweigh these short-term neonatal problems.
Other newer antidepressants
Preliminary data suggest venlafaxine is not associated with congenital abnormality. The safety during pregnancy of mirtazapine, moclobemide, nefazodone and reboxetine has not been adequately studied.
Some authorities regard nortriptyline as the TCA of choice during pregnancy due to its lower likelihood of anticholinergic adverse effects and orthostatic hypotension, as well as the ability to measure maternal serum levels.
In the neonate, anticholinergic adverse effects have occasionally been observed, as has a withdrawal reaction (irritability, insomnia, fever and colic). Abrupt discontinuation of clomipramine in pregnancy has been associated with premature delivery, and subsequent convulsions in the newborn. Case reports suggest that a single dose (mg/kg basis) of oral clomipramine for the newborn leads to cessation of convulsions by the third day.
The safety during pregnancy of mianserin and irreversible nonselective monoamine oxidase inhibitors (MAOIs) has not been adequately studied.
Lithium
The use of lithium within the first trimester has, in previous studies, been linked to fetal abnormalities. In particular, the risk of serious cardiac malformations was thought to be very significantly increased. Animal experiments have demonstrated marked teratogenic effects of lithium. More recent reviews have suggested that earlier estimates of risk in humans may have been overestimated, and at least one authority has concluded that the benefits of lithium prophylaxis during pregnancy may, in some cases, outweigh the risks. Nevertheless, most authorities still recommend against the use of lithium during pregnancy, although the risk of congenital heart defects may only be increased slightly. It has been suggested to avoid lithium until cardiogenesis is complete, ie about 50 days postconception, and then resume if necessary.
In general, patients who are on lithium and who wish to become pregnant should have their lithium gradually withdrawn before conception occurs. If the pregnant patient develops symptoms and is in need of pharmacological treatment, then antidepressants and antipsychotic drugs can be prescribed for depressive or manic symptoms.
If a woman taking lithium wishes to conceive, the problem should be discussed with her. If a woman conceives while on lithium, the potential risks of illness recurrence after withdrawal of this medication must be balanced against the teratogenic risk to the fetus from lithium. If exposure has occurred in the first trimester, cardiac abnormalities can be investigated antenatally using ultrasound and echocardiography. These technologies have become increasingly specialised in recent years and expert advice should be sought.
Renal clearance increases during pregnancy and falls abruptly after delivery. Careful monitoring of serum lithium concentrations and dosage regimens is indicated. At delivery, lithium has been associated with the neonate being 'floppy' and less responsive.
The puerperium is a time of high risk of relapse of mania or depression. Prophylactic treatment with lithium immediately after delivery is recommended by some authorities for patients with bipolar disorder who have been well-controlled on lithium. However, the implications for breastfeeding must also be considered.
After the first trimester, anxious patients who do not respond to counselling or sleep hygiene measures may benefit from the intermittent use of low dose benzodiazepines as hypnotics. There is some evidence that oxazepam or temazepam, being shorter-acting drugs, are preferable to longer-acting benzodiazepines such as diazepam.
If benzodiazepines are taken in late pregnancy, they can cause neonatal drowsiness, respiratory depression and hypotonicity (the floppy infant syndrome). Neonatal withdrawal symptoms have also been reported.
There are no available data to enable a definitive judgement to be made about the safety of zopiclone and zolpidem during pregnancy. However, evidence from small series suggests that zopiclone is not a major human teratogen.
Attacks of asthma during pregnancy may reduce the amount of oxygen available to the fetus, so it is particularly important that asthma should be well controlled. Severe exacerbations should be treated promptly with conventional therapy. Prolonged courses of high-dose oral corticosteroids should be avoided.